A range of different approaches have been used for modifying the structure of insulinotropic peptides, such as glucagon-like peptide 1 (GLP-1) and exendin-4 compounds, in order to provide a longer duration of action in vivo.
WO 96/29342 discloses peptide hormone derivatives wherein the parent peptide hormone has been modified by introducing a lipophilic substituent in the C-terminal amino acid residue or in the N-terminal amino acid residue.
WO 99/43708 discloses exendin derivatives wherein at least one amino acid residue has a lipophilic substituent attached.
WO 00/69911 discloses activated insulinotropic peptides to be injected into patients where they are supposed to react with blood components to form conjugates and thereby allegedly providing longer duration of action in vivo.
WO 02/46227 discloses GLP-1 and exendin-4 analogs fused to human serum albumin in order to extend in vivo half-life.
Many diabetes patients particularly in the type 2 diabetes segment are subject to so-called “needle-phobia”, i.e. a substantial fear of injecting themselves. In the type 2 diabetes segment most patients are treated with oral hypoglycaemic agents, and since insulinotropic peptides are expected to be the first injectable product these patients will be administered, the fear of injections may become a serious obstacle for the widespread use of exendin-4 compounds. Thus, there is a need to develop new exendin-4 compounds which can be administered less than once daily, e.g. once every second or third day preferably once weekly, while retaining an acceptable clinical profile.